Donor Specific HLA Alloantibodies in Liver Transplantation

NCT ID: NCT02784080

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Total Enrollment: 858 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2015-08-15
• Study Completion Date: 2024-12-31

Brief Summary

The aim is to evaluate the impact of donor specific HLA alloantibodies (DSA) on all-cause mortality and re-transplantation, early allograft dysfunction, acute and chronic rejection, fibrosis, vascular, and biliary complications. Furthermore, all biopsies will be C4d stained. The hypothesizes is that donor specific HLA alloantibodies facilitate an immune mediated damage to the liver allograft that impairs function and lead to various complications.

The investigators will do a prospective blinded multicenter cohort study in the Scandiatransplant organ sharing organization region.

Both preformed, persistent, and de novo donor specific HLA alloantibodies will studied. Blood samples will be taken immediately prior to transplantation, and 14 days, 3 months, and 1 year after transplantation. All liver biopsies performed during the study period will be evaluated for a humoral component and blood samples will be obtained prior to liver biopsies to investigate the presence of DSA.

Investigations will be fully blinded for the treatment responsible doctors.

Detailed Description

The outcome after liver transplantation has improved drastically over time, but this development has stagnated in recent years to a graft failure rate of 9-15 % within the first year and approximately 20-30 % at 5 years [1]. The primary goal is to improve the outcome after liver transplantation.

The impact of donor specific antibodies (DSA) on all-cause mortality and re-transplantation, early allograft dysfunction, acute and chronic rejection, vascular and biliary complications and fibrosis will be investigated.

Objectives:

1. The primary objective is to investigate if DSA both pre-formed, persistent, and de novo affect survival and allograft loss. For patients diagnosed with HLA antibodies a standard Luminex single antigen IgG analysis, a Luminex C1q and an IgG3 single antigen assay will be performed.

2. The secondary objective is to investigate if donor specific antibodies, both pre-formed, persistent, and de novo increase the risk of early allograft dysfunction, acute and chronic rejection, fibrosis, de novo autoimmune hepatitis (pediatric patients only), vascular and biliary complications. All liver biopsies will be stained by C4d and a DSA analysis will be undertaken.

3. Continuous measurements will be used to establish the kinetics of both preformed og de novo DSA after liver transplantation.

Pediatric patients will be analyzed separately.

In 2021 it was decided to split the study in a preformed and de novo study.

Preformed DSA

1. Our primary objective is to investigate if preformed and persistent DSA class I and II affect survival and re-transplantation.

2. The secondary objective is to investigate if preformed and persistent DSA class I and II is correlated with increased risk of acute rejection and early allograft dysfunction.

Preformed DSA will be analysed in 4 different ways separately for donor specific HLA class I and class II antibodies.

1. Dichotomous analysis defined as any DSA class I or II MFI >1000 is considered positive.

2. Number of different class I or II DSA will be analyzed as an ordinal variable.

3. A continuous variable by MFI, as a sum of all. Homozygous donors will not be accounted for.

4. Analysis will be done for no antibodies versus: 1) HLA-DQ (including DRB5 subtypes) 2) HLA-DR 3) HLA-DQ and -DR. Both as categorical and binary.

Conditions

Complication of Transplanted Liver

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

HLA-alloantibodies exposure

Preformed, persistent, and de novo HLA-alloantibody exposure in the whole cohort.

HLA-alloantibodies exposure

Intervention Type: OTHER

Following analyzes will be done:

LABScreen® Single Antigen, One Lambda, CA

C1qScren™, One Lambda, CA (planned for later study)

PE-conjugated IgG3 antibody (planned for later study)

LABScreen® Mixed, One Lambda, CA (never analysed in the study)

Interventions

HLA-alloantibodies exposure

Following analyzes will be done:

LABScreen® Single Antigen, One Lambda, CA

C1qScren™, One Lambda, CA (planned for later study)

PE-conjugated IgG3 antibody (planned for later study)

LABScreen® Mixed, One Lambda, CA (never analysed in the study)

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Undergo a liver transplanted during the study period.
• Pre-transplant serum sample of minimum 4 ml (relevant for pediatric patients)
• Informed consent is given.

Exclusion Criteria

• Withdrawal of informed consent.
• Blinding broken in a non-protocoled manner the patient will be excluded.

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sahlgrenska University Hospital

OTHER

Sponsor Role: collaborator

Karolinska Institutet

OTHER

Sponsor Role: collaborator

Helsinki University Central Hospital

OTHER

Sponsor Role: collaborator

Oslo University Hospital

OTHER

Sponsor Role: collaborator

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Andreas Arendtsen Rostved

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Allan Rasmussen, MD

Role: STUDY_CHAIR

Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, Denmark

Andreas A Rostved, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, Denmark

Helle Bruunsgaard, MD, DMSc

Role: STUDY_DIRECTOR

Department of Clinical Immunology, Centre of Diagnostic Investigation, Rigshospitalet - Copenhagen University Hospital

Locations

Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital

Copenhagen, , Denmark

Transplantation and Liver Surgery Clinic, Helsinki University Hospital

Helsinki, , Finland

Department of Transplantation Medicine, Oslo University Hospital

Oslo, , Norway

Surgery Department, Transplantation and Liver Surgery Unit, Sahlgrenska University Hospital

Gothenburg, , Sweden

Division of Transplantation Surgery, Karolinska Institutet

Stockholm, , Sweden

Countries

Denmark; Finland; Norway; Sweden

References

Kim WR, Smith JM, Skeans MA, Schladt DP, Schnitzler MA, Edwards EB, Harper AM, Wainright JL, Snyder JJ, Israni AK, Kasiske BL. OPTN/SRTR 2012 Annual Data Report: liver. Am J Transplant. 2014 Jan;14 Suppl 1:69-96. doi: 10.1111/ajt.12581.

Reference Type: BACKGROUND

PMID: 24373168 (View on PubMed)

Other Identifiers

H-15007823

Identifier Type: -

Identifier Source: org_study_id